As a symptom exhibited by many diseases, pain is a reaction when adverse stimulation or damage occurs to the body, which can prevent the body from being harmed. But intense pain such as myocardial infarction, advanced cancer, and trauma may not only afflict the patients, but cause severe disorders to their physiological functions, or even shock and death. Therefore, it is necessary to apply painkillers to reduce harm and improve patients' quality of life.
Currently, analgesics clinically used can be divided mainly into narcotic analgesics (opioid analgesics) and non-narcotic analgesics (antipyretic analgesics), in which, the former have stronger effects but with a series of adverse reactions like addiction, drug resistance, respiratory depression, nausea and constipation, especially limitations on the use of such drugs due to possible opioid abuse and the generation of drug dependence. Though with fewer side effects, the latter just exhibit quite limited analgesic effects in general. On the whole, these known analgesics are still not desirable at present; thus, it is valuable to develop a new generation of analgesics that have good analgesic activity but without addiction.
As the dry tuber of papaveraceae corydalis yanhusuo and with the effects of blood activation, qi invigoration and pain relief, Corydalis yanhusuo is commonly applied in treating diseases like chest and hypochondriac pain, abdominal pain, amenorrhea and dysmenorrhea, postpartum blood stasis as well as swelling and pain due to falling and contusions, which is a famous analgesic traditional Chinese medicine with a long medicinal history. In the 1950s and 1960s, Jin Guozhang et al. had conducted systematic research on the neuropharmacology of Corydalis yanhusuo and found out that it had a series of tertiary amine type alkaloids which boasted analgesic activity, including corydaline, tetrahydropalmatine, protopine and corydalis L, etc. Wherein, with the strongest analgesic effect, L-tetrahydropalmatine (1-THP) was recognized as the main effective component in Corydalis yanhusuo's analgesic effect. Its analgesic effect was weaker than pethidine but stronger than antipyretic analgesics, and particularly, 1-THP had good effects on chronic and persistent dull pain. After that, 1-THP was further discovered to have a significant calming effect, showing the potential for treating nervous system diseases such as schizophrenia. The analgesic effect of 1-THP has no relation to opioid receptors or the prostaglandin system, whose mechanism of action is greatly different from that of narcotic analgesics and antipyretic analgesics. In 1977, 1-THP, as a new drug belonging to those with analgesic and sleep-conducive effects, was incorporated into the Pharmacopoeia of the People's Republic of China (PPRC), mainly used for dull pain, headaches, dysmenorrhea and labor pain, etc. resulting from gastrointestinal and hepatobilliary system diseases, as well as other medical diseases, which features low toxicity, high safety and no addiction, becoming the first nervous system drug successfully developed by the application of modern science and technology since the establishment of the People's Republic of China and also an example of sorting out Chinese medicine through science successfully. However, until the late 1980s, Jin Guozhang et al. did not prove that 1-THP's analgesic and calming effects were related to its blocking activity to dopamine D2 receptor. The blocking effect covers two target areas, specifically, it blocks postsynaptic D2 receptors in the nucleus accumbens (Nac) target area to inhibit the effect of dopamine transporter (DAT), while blocking D2 receptors in the hypothalamic arcuate nucleus (Arc) target area, which can increase the function of endogenous opioid peptides (END) of periaqueductal gray (PAG). Since the dopamine receptors of Nac are the common target area for addiction to opioids, cocaine, and amphetamines, the blocking effect of 1-THP's dopamine D2 receptor can also be used for drug addiction prevention and withdrawal. Over recent years, the practice of 1-THP in preventing the said three drugs has achieved some satisfactory achievements via fundamental and clinical research at home and abroad, which exhibits good potential.
Apart from tertiary amine type berberine, Corydalis yanhusuo also contains many quarternary ammonium type berberine compounds, such as dehydrocorydaline, palmatine, berberine and jatrorrhizine, which have been reported on their activities in aspects such as anti-gastric ulcers, anti-bacteria, hypoglycemic effect, and anti-tumor. But so far, there has been no report saying that quarternary ammonium type berberine has analgesic activity.
From our multi-model systematic screen of Corydalis yanhusuo's analgesic activity, it is discovered that some quarternary ammonium type berberines have dopamine D2 receptor blocking activity. Among them, the dehydrocorybulbine (DHCB) further contains weak opioid receptor activity, for which related animal experiments indicate that its analgesic and calming activities are stronger than those of 1-THP, while the acting duration and the drug resistance property are superior to that of morphine, which has good prospect in the application of analgesia. In addition, due to its dopamine receptor activity similar to that of 1-THP, other nervous system diseases associated with dopamine receptor system such as depression and drug addiction can be predicted, which is promising as well.